(a) Field of Invention
The present invention relates to gastrointestinal compositions containing mixtures of plantago and of pectin, to a process for preparing said compositions and to the use thereof for the inhibition and/or prevention and/or alleviation of certain gastrointestinal disorders. More specifically, the gastrointestinal compositions of this invention are useful for inhibiting the occurrence of gastroduodenal ulcers and for alleviating certain symptoms of gastrointestinal distress associated with gastritis or with the presence of such ulcers. In particular, they are surprisingly useful in preventing the recurrence of gastroduodenal ulcers following the discontinuation of therapy with anti-ulcer drugs, and for reducing the incidence and severity of undesirable side effects of said anti-ulcer drugs. Moreover, they are also useful in alleviating discomfort caused by gastroesophageal reflux and for regularizing bowel movements in constipated as well as in diarrheal patients, with concomitant relief from discomfort and pain. The gastrointestinal compositions are particularly distinguished by the absence of undesirable side effects.
(b) Prior Art
Statistics Canada, Causes of Death, Vital Statistics, Vol. IV, Statistics Canada, Health Division, 1984, pp. 96-99 reported that 16,352 people died in Canada from gastrointestinal diseases in 1982. It is not known how many people in Canada are suffering each year from gastroduodenal ulcers. It is estimated that gastroduodenal ulcers (peptic ulcers) affect between 5% and 6% of adults in the U.S.A. with approximately 300,000 new cases diagnosed each year, Jadhav, G. R. et al: Drug Therap., p. 183, Jan 1983. Total digestive disorders afflict nearly 20 million Americans, at an estimated annual cost of over 8 billion dollars in medical expenses alone, National Commission on Digestive Diseases, Vol. I. U.S. Dept. of Health, Education and Welfare. Public Health Service, NIH, DHEW, Publication No. NIH: 79-1878, Jan. 1979, p. 1. In some countries it is believed that almost 20% of individuals may suffer from peptic ulceration during their lifetime, D. W. Piper, Book Reviews, Practitioner 227:529, 1983. Various factors such as stress, diet, some drugs, alcohol, smoking, inheritence factors etc. seem to be responsible for causing peptic ulcers. The importance of the problem, both from the point of view of public health as well as from that of the national economy, is undoubtedly of a very high order.
In view of the common belief that gastroduodenal ulcers were mainly caused by excess production of digestive acids, research for an effective ulcer therapy has traditionally focussed upon inhibiting those acids, although it is now known that many patients suffering from gastroduodenal ulcers secrete amounts of acid which are within, or even below, normal physiological values, (see e.g. A. L. Blum et al., Pt. II, Acta Hepato-Gastroenterol. 22, 123, 1975 and J. Rhodes, Gastroenterology 63, 171, 1972). Attempts to strengthen the ability of the gastroduodenal mucosa to resist those acids seem to have been largely neglected, although one of the fathers of modern physiology, Claude Bernard (1813-1878) had already pointed out the importance of that resistance when he stated that " . . . the epithelium of the gastric mucosa, especially the glutinous mucus which covers the inner wall, thus encloses the gastric juices as in a vase, as impermeable as though it were made of porcelain . . . " (cited by P. E. O'Brien, Clin. Surg. Int. 7, Chapter 3, p. 28, D. C. Carter, Ed. Churchill Livingstone, Edinburgh London Melbourne and New York 1983). However, several types of anti-ulcer agents such as H2-receptor antagonists, (e.g. cimetidine, ranitidine), coating agents (e.g. sucralfate, tripotassium di-citrato-bismuthate), certain anti-inflammatory agents (e.g. carbenoxolone), and antacids appear to be effective in healing gastric and/or duodenal ulcers when administered at recommended doses, and certain cytoprotective agents such as prostaglandins E-2 and I-2 would appear to be promising are presently under study. However, all of those agents exhibit certain undesirable side effects which are not shown by the gastrointestinal compositions of this invention, and which will be discussed below.
The histamine H.sub.2 -receptor antagonists cimetidine and ranitidine are potent systemic anti-ulcer drugs which have to be administered in fairly high doses for several weeks in order to show significant rates of healing of gastroduodenal ulcers. However, it is now well known that those drugs cannot keep the ulcers healed unless long term therapy is used (see e.g. A. E. Read, Practitioner 227, 535, 1983) and the manufacturers of ranitidine, conscious of the dangers and the disadvantages of prolonged administration of the drug, are recommending that endoscopic examination should be carried out after two weeks of medication " . . . to spare many patients an additional period of treatment . . . " (see Physician's Desk Reference (PDR) 1984, p. 985). Evidence is now accumulating that patients with chronic duodenal ulcers will have to be treated with histamine H2-receptor antagonists for many years, and possibly permanently (G. C. Clark, Practitioner 227, 543, 1983). For those reasons many physicians are now reassessing the value of those drugs, as they are seriously concerned about the concept of permanent treatment of a generally benign disease with potent drugs (see G. C. Clark, cited above). A number of undesirable side effects have also been observed and have been summarized by G. L. Kauffman, Jr. in J. Clin. Gastroenterol. 3 (Suppl. 2), 95, 1981; they include diarrhea, muscular pain, dizziness, rash, mild gynecomastia, mental confusion, lethargy, restlessness, disorientation, agitation, hallucination, twitching, and apnea. In addition, ranitidine is also stated to cause a significant incidence of headache, as well as occasional malaise, constipation, nausea, and abdominal pain, see PDR 1984 p. 985 cited above. However, it would appear that the most serious disadvantage of the histamine H2-receptor antagonists is the fact that gastroduodenal ulcers which had healed under treatment with those drugs frequently recur after cessation of medication. G. R. Jadhav et al., cited above, reported that the rate of recurrence was 42 percent to 70 percent three months after discontinuation of cimetidine therapy, and 74 percent to 90 percent after one year, and H. P. Roth, Gastroenterology 61, 570, 1971 reported that 42 percent of ulcer patients experienced recurrence of ulcers within six months. The manufacturers of cimetidine recommend administration of reduced doses of the drug (400 mg at bedtime only instead of 300 mg four times per day) as a prophylactic regimen against the recurrence of ulcers (see PDR 1983, pp. 1912 and 1913), but such a regimen would hardly seem to be conducive to the avoidance of undesirable side effects.
Prostaglandins E-2 and I-2 are believed to be of significant importance in maintaining gastric mucosal integrity and thus to act as cytoprotective agents. Robert et al., Gastroenterology 77, 433, 1979 have also reported that several analogues thereof appear to be effective in preventing gastric mucosal injury induced by a variety of agents, and Konturek et al., Gut 22, 283, 1981 have shown that administration of Prostaglandins E-2 and I-2 prevents gastric mucosal damage induced by aspirin. Those compounds are currently undergoing clinical evaluation for the treatment of peptic ulcers, but it is well known that they cause a number of undesirable side effects among which diarrhea, nausea, and vomiting are the most serious.
Among the systemic anti-inflammatory drugs presently available only carbenoxolone would appear to act locally on the stomach, possibly by stimulant actions upon mucin production and the enzyme processes involved in cellular regeneration, see Martindale Extra Pharmacopoeia 27th edition, 1977, p. 299. G. L. Kauffman, Jr. cited above has reported that carbenoxolone appears to increase the life span of epithelial cells; that it alters the carbohydrate composition of gastric mucus: topical application of carbenoxolone to the stomach lining of rats increased the thickness of the mucous layer by 80 percent; that it may affect the permeability of the gastric mucosa to hydrogen ions; and that it inhibits peptic activity in the gastric luminal fluid without inhibiting gastric acid secretion; that it is effective in the treatment of gastric ulcers, and that it has beneficial effects in cases of duodenal ulcers; that a comparison of the effects of cimetidine and of carbenoxolone upon gastric ulcers had shown 78 percent healing following cimetidine treatment as against 52 percent with carbenoxolone; that the rate of recurrence of gastric ulcers following discontinuation of carbenoxolone treatment was about 40 to 50 percent, and that administration of maintenance doses of carbenoxolone was capable of reducing the recurrence rate from 46 percent to 25 percent; and that administration of maintenance doses of carbenoxolone reduced the rate of recurrence of duodenal ulcers to 21 percent and was thus more effective than the maintenance regimen using cimetidine in patients previously treated with cimetidine in which the recurrence rate was found to be 48 percent. However, carbenoxolone exhibits a number of undesirable side effects of which sodium and water retention with ensuing edema and weight gain, alkalosis, hypertension, and hypokalemia appear to be the most serious and are reported to occur in about 25 to 30 percent of patients, see Martindale, and also G. L. Kauffman, Jr., both cited above. In view of the seriousness of the above side effects a maintenance regimen using carbenoxolone may possible reduce their incidence and severity, but it may hardly be expected to eliminate them altogether.
As an example of a coating agent sucralfate, a sucrosepolysulfate aluminum complex, inhibits pepsin activity in gastric juice and has been shown in vitro to absorb bile salts; it is only minimally absorbed from the gastrointestinal tract and the small amounts which are absorbed are excreted primarily in the urine; it forms an ulcer-adherent complex with the proteinaceous exudate at the site of the ulcer, and experiments in vitro have demonstrated that a sucralfate-albumin film provides a barrier to the diffusion of hydrogen ions (see PDR 1984, pp. 1164-1165). Sucralfate is an effective non-systemic agent for the therapy of duodenal ulcers (D. Hallander, Int. Cong. Gastroenterol. 1982, No. 2205, p. 548) and of gastric ulcers (M. E. Denyer, Practitioner 227, 633, 1983), but although the ulcers may heal after a few weeks of treatment there is no permanent cure: Denyer, cited above, has shown that the rate of recurrence in patients observed 9-12 months after discontinuation of sucralfate medication is about the same as that following treatment with cimetidine, viz., about 70 percent in both groups after one year. However, patients which had been initially treated with sucralfate showed a significantly longer mean of duration of remission (7.3 months) than those initially treated with cimetidine (4.6 months), see Inpharma Aug. 27, 1983, pp. 17-18. The most frequently occurring undesirable side effect of sucralfate medication was constipation reported by 2.2 percent of all patients, with diarrhea, nausea, gastric discomfort, indigestion, dry mouth, rash, pruritus, back pain, dizziness, sleepiness, and vertigo being reported occasionally, see PDR 1984, cited above. Xerostomia, skin eruptions, and abdominal pain associated with acute dosing of sucralfate have also been reported, see Inpharma, Recent Reviews, Sept. 18, 1982, and Sherman et al., Am. J. Gastroenterol. 78, 210, 1983 have reported that sucralfate lowers phosphate levels, probably by phosphate binding in the intestines, and that the drug would appear to be another factor predisposing the ulcer patient to hypophosphatemia and its attendant complications.
Tripotassium di-citrato bismuthate (TDB), a colloidal bismuth preparation also called bismuth subcitrate, is another example of a coating agent. It is believed to possess "ulcer-insulating" and anti-pepsin activities, see T. R. Wilson, Postgrad. Med. J. 51(Suppl. 5), 18, 1975. Van Trappen et al., Gut 21, 329, 1980 have reported that it is more effective than placebo in healing duodenal ulcers, and that it is as effective as cimetidine or slightly superior in that respect. Similar results have also been obtained by Tanner et al., Med. J. Aust. 1, 1, 1979 in patients suffering from gastric ulcers. Concerning the recurrence of ulcers, G. L. Kauffman, Jr., cited above, reported the results of a limited study which showed that the rate of recurrence was higher in patients initially treated with cimetidine than in those initially treated with TDB. Undesirable side effects include blackening of the stool (which may be confused with melena), and sometimes also darkening of the tongue. Furthermore, TDB has an ammoniacal odour which patients may find to be objectionable.
A wide variety of antacids are commonly available, most of them containing aluminum hydroxide, magnesium oxide or hydroxide or trisilicate, or calcium carbonate, or mixtures thereof. Some of them are effective in reducing pain and discomfort associated with gastroduodenal ulcers, and all of them are designed to raise gastric pH levels. Howwever, repeated dosing at short intervals with some of those antacids, a practice which is often resorted to by patients which are not under surveillance, may result in gastric pH levels which exceed the safe limits and which may lead to acid rebound and thus cause additional damage. Antacids containing aluminum hydroxide may cause constipation, and those containing magnesium compounds may cause diarrhea. Furthermore, alkalosis and/or hyper-aluminum, hyper-magnesium, or hyper-calcium states may be observed in patients suffering from renal impairment, see G. L. Kauffman, Jr., cited above.
The above review of the Prior Art shows that the systemic anti-ulcer drugs presently used in the treatment of gastroduodenal ulcers cause a considerable incidence of undesirable side effects, and that even the coating agents and the antacids are not free from causing certain adverse reactions. M. E. Denyer, cited above, has said that " . . . in peptic ulcer therapy, the 1970's could be described as the decade of the acid inhibitors. Perhaps the pendulum is now swinging back and the 1980's will prove to be the decade of the mucosal protective agents . . . ". The present invention is directed towards the latter aim, as will be shown below.